from Science Translational Medicine 17 May 2017: Vol. 9, Issue 390
More than 2 million bone-grafting procedures are performed each year using autografts or allografts. However, both options carry disadvantages, and there remains a clear medical need for the development of new therapies for massive bone loss and fracture nonunions.
We hypothesized that localized ultrasound-mediated, microbubble-enhanced therapeutic gene delivery to endogenous stem cells would induce efficient bone regeneration and fracture repair. To test this hypothesis, we surgically created a critical-sized bone fracture in the tibiae of Yucatán mini-pigs, a clinically relevant large animal model. A collagen scaffold was implanted in the fracture to facilitate recruitment of endogenous mesenchymal stem/progenitor cells (MSCs) into the fracture site.
Two weeks later, transcutaneous ultrasound-mediated reporter gene delivery successfully transfected 40% of cells at the fracture site, and flow cytometry showed that 80% of the transfected cells expressed MSC markers. Human bone morphogenetic protein-6 (BMP–6) plasmid DNA was delivered using ultrasound in the same animal model, leading to transient expression and secretion of BMP-6 localized to the fracture area. Micro-computed tomography and biomechanical analyses showed that ultrasound-mediated BMP-6 gene delivery led to complete radiographic and functional fracture healing in all animals 6 weeks after treatment, whereas nonunion was evident in control animals.
Collectively, these findings demonstrate that ultrasound-mediated gene delivery to endogenous mesenchymal progenitor cells can effectively treat nonhealing bone fractures in large animals, thereby addressing a major orthopedic unmet need and offering new possibilities for clinical translation.
Author info: Bez M1,2, Sheyn D2,3, Tawackoli W2,3,4,5, Avalos P3, Shapiro G1, Giaconi JC6, Da X4, David SB2,3, Gavrity J7, Awad HA7, Bae HW2, Ley EJ2, Kremen TJ2,8, Gazit Z1,2,3,8, Ferrara KW9, Pelled G1,2,3,4,5, Gazit D10,2,3,4,5,8.
Regenerative Orthopedic news strives to bring you the latest science updates. If you have regenerative orthopedic news you’d like to post, please contact Dr. Kohlstadt.